Microwave-assisted synthesis of Nitroketene N,S-Arylaminoacetals

ARTICLE

Microwave-assisted synthesis of Nitroketene N,S-Arylaminoacetals

Diego P. Sangi; Arlene G. Corrêa^*

Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos-SP, Brazil

ABSTRACT

In this paper we report the use of microwaves as heat source to promote the synthesis of a series of nitroketene N,S-acetals with good to excellent isolated yields. These compounds are very useful intermediates for synthesizing nitrogen-containing heterocycles.

Keywords: nitroketene N,S-arylaminoacetals, microwaves, quinoxalines

RESUMO

Neste trabalho nós relatamos o uso de microondas como fonte de energia para promover a síntese de uma série de nitroeteno N,S-acetais com bons rendimentos. Estes compostos são intermediários muito úteis para a síntese de sistemas heterocíclicos nitrogenados.

Introduction

Nitroketene N,S-acetals are very useful intermediates for synthesizing nitrogen-containing heterocycles, such as 2-amino-3-nitro-4H-chromenes,¹ 4-imino-3,4-dihydropyrimidin-2(1H)-ones,² and quinoxalines.^3,4 Substituted quinoxalines have displayed a large number of biological activities including antiviral, antibacterial and as kinase inhibitors.^5,6 1-Methylamino-l-methylthio-2-nitroethene is a crucial intermediate for the manufacture of ranitidine.⁷

The synthesis of nitroketene N,S-acetals (3) are usually performed by reaction of l,l-bis(methylthio)-2-nitroethene (1) with one equivalent of several primary or secondary amines (Scheme 1).^1,8,9 A second approach to the synthesis of nitroketene N,S-acetals is performed by adding nitromethane anion to methyl isocyanate, followed by S-methylation.^8,10 In a different approach, nitromethane has been condensed with bis(methylthio)methaneimine in the presence of a rare-earth exchanged NaY zeolite.¹¹

Nowadays, it is noteworthy to connect research in chemistry and environmental protection. One of the principles of green chemistry is energy efficiency, thus the synthetic methods should be conducted whenever possible at room temperature and pressure, to reduce the energy spent during a chemical process. One option is to replace the conventional heating by alternative energy sources such as microwave.¹²

Microwave-assisted organic synthesis has had a profound impact on the way that chemists approach organic and parallel synthesis. Clearly, reductions in reaction times, improved yields and suppression of side products, relative to conventional thermal heating, are some benefits of this emerging technology.^13-15

In this paper we report the use of microwaves as heat source to promote the synthesis of a series of nitroketene N,S-acetals with good to excellent isolated yields.

Results and Discussion

In a ongoing program towards the synthesis of quinoxalines, we investigated the reaction of nitroethene 1 with aniline using ethanol as solvent and microwave (MW) irradiation (Scheme 1). In our first trial, we obtained 43% yield of the desired product after 30 min at 110 ^oC and 70 W. We then performed a series of experiments in order to optimize this result, which are summarized in Table 1. We observed that the rate of conversion of reagents increased with temperature and power of microwave (entries 1 and 2); however when the temperature increased up to 140 ^oC and power to 150 W, by-products were formed (entry 3). Thus, we decided to investigate the time reaction by keeping temperature at 110 ^oC and power at 70 W (entries 4, 5 and 6). The desired product was obtained in 85% yield, gradually increasing the reaction time, without formation of by-products after 90 min. We confirmed the optimization with p-methoxyaniline, which furnished higher yields in the same conditions.

After optimizing the reaction, we performed the coupling of different amines possessing electron donating and electron withdrawing groups to evaluate the scope of this protocol. Good to excellent isolated yields were obtained in most cases, excepting the reaction with anilines 2k and 2n, probably due to the presence of the strong electron withdrawing group. We have also observed that groups in the 2-position may cause steric hindrance effect, as for example for anilines 2d and 2g (Table 2). The reaction with ciclohexylamine (4) was performed (Scheme 2) and furnished the corresponding N-[1-(methylthio)-2-nitroethenyl]-cyclohexanamine (5) in 98% yield.

Due to the failure of the methodology as a result of the presence of strongly electron-withdrawing groups, we performed further tests with the 4-trifluoromethylaniline (Table 3). Therefore, we attempt the same procedure by using higher power and temperature (entry 2). We have also tested different solvents (entries 3 and 4). In general a reaction medium with a high loss tangent (tan d) at the standard operating frequency of a microwave synthesis reactor (2.45 GHz) is required for good absorption and, consequently, for efficient heating.¹³ However, even in this case we have gotten just unreacted starting materials and traces of the desired products.

All products were characterized by ¹H and ¹³C NMR, infrared, GCMS spectra and melting point. The spectroscopic data were identical with those described in the literature.^3,4,9,16-20 The geometry of the 1-aryl-1-methylthio-nitroketenes are probably all E in which orientation intramolecular hydrogen bonding is possible; this was verified for 3e by the observation of an nOe between the thiomethyl and the vinylic hydrogens.²¹

Conclusions

In summary, we have demonstrated that reactions between amines and l,l-bis(methylthio)-2-nitroethene (1) employing microwave heating is an advantage method since desired products can be obtained in good yields and shorter reaction time when compared to the conventional heating. This protocol afforded a series of nitroketene N,S-acetals (3) in with good to excellent yields.

Experimental

Unless otherwise noted, all commercially available reagents were purchased from Aldrich Chemical Co. and used without purification. ¹H and ¹³C NMR spectra were recorded on a Bruker ARX-400 (400 and 100 MHz respectively). The IR spectra refer to tablets in KBr and were measured on a Bomem M102 spectrometer. Mass Spectra were recorded on a Shimadzu GCMS-QP5000. Elemental analyses were performed on a Fisons EA 1108 CHNS-O. Analytical thin-layer chromatography was performed on a 0.25 mm film of silica gel containing fluorescent indicator UV₂₅₄ supported on an aluminum sheet (Sigma-Aldrich). Flash column chromatography was performed using silica gel (Kieselgel 60, 230-400 mesh, E. Merck). Gas chromatography was performed in a Shimadzu GC-17A with N₂ as carrier and using a DB-5 column. Melting points were performed in Microquimica MQAPF - 301.

Typical experimental procedure: nitroethene 1 (30 mg 0.182 mmol), amine 2 (0.182 mmol) and ethanol (1 mL) were placed in a glass tube, purged with oxygen-free nitrogen during 10 min sealed and irradiated in during 90 min in a CEM Discovery® focused microwave oven at 110 ^oC and 70 W. The nitroketene N,S-acetals 3 were purified by flash chromatography employing hexanes:ethyl acetate (4:1 ratio) as eluent.

3,4,5-Trimethoxy-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3a )¹⁷

¹H NMR (400 MHz, CDCl₃): δ 2.39 (s, 3H), 3.86 (s, 6H), 3.87 (s, 3H), 6.52 (s, 2H), 6.68 (s, 1H), 11.82 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.77, 56.36, 60.98, 103.66, 107.82, 131.70, 153.65, 163.40, 170.87. IR (KBr) ν_max/cm^-1: 3159.67, 3066.59, 3008.73, 2947.01, 2842.87, 1595.01, 1548.73, 1415.65, 1330.79, 1234.35, 1126.35, 1004.84, 671.18. GC-MS (70 eV) m/z (%): 300 (M⁺, 10), 266 (80), 251 (100), 223 (33), 194 (37), 167 (20). (Found: C, 47.34; H, 5.56; N, 9.17; S, 10.18. Calc. for C₁₂H₁₆N₂O₅S: C, 47.99; H, 5.37; N, 9.33; S, 10.68%).

3,5-Dimethoxy-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3b )^3,4

¹H NMR (400 MHz, CDCl₃): δ 2.39 (s, 3H), 3.80 (s, 6H), 6.45-6.42 (m, 3H), 6.68 (s, 1H), 11.80 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.81, 55.58, 100.11, 103.98, 108.08, 137.82, 161.32, 162.99. IR (KBr) ν_max/cm^-1: 3170.70, 3093.59, 2995.23, 2839.01, 1612.37, 1542.94, 1471.58, 1427.22, 1319.21, 1195.78, 1153.35, 1060.77, 972.05, 848.62, 690.47, 597.89. GC-MS (70 eV) m/z (%): 270 (M⁺, 12), 236 (52), 221 (100), 177 (66), 137 (93), 122 (70), 107 (45).

3-Methoxy-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3c )^3,4

¹H NMR (400 MHz, CDCl₃): δ 2.39 (s, 3H), 3.83 (s, 3H), 6.70 (s, 1H), 6.90 (t, 1H, J 2.15 Hz), 6.92-6.87 (m, 2H), 7.33 (t, 1H, J 8.26 Hz), 11.82 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.71, 54.01, 111.44, 113.76, 117.89, 130.09, 137.19, 160.25, 163.28. IR (KBr) ν_max/cm^-1: 3159.17, 3070.45, 2995.23, 1602.73, 1546.80, 1465.79, 1417.58, 1330.79, 1269.07, 1222.78, 1157.20, 958.55, 848.62, 684.68, 570.89, 532.31. GC-MS (70 eV) m/z (%): 240 (M⁺, 12), 206 (41), 159 (38), 147 (64), 107 (100), 77 (99).

2,5-Dimethoxy-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3d )^3,4

¹H NMR (400 MHz, CDCl₃): δ 2.40 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 6.82 (dd, 1H, J₁9.27, J₂2.98 Hz), 6.90 (d, 1H, J 9.27 Hz), 7.01 (d, 1H, J 2.98 Hz), 6.71 (s, 1H), 11.79 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.86, 55.91, 56.33, 108.39, 112.33, 112.41, 113.13, 125.96, 147.24, 153.18, 162.78. IR (KBr) ν_max/cm^-1: 3161.10, 3074.31, 2995.23, 1544.87, 1508.22, 1473.51, 1411.79, 1321.14, 1226.64, 1114.77, 1045.34, 802.33, 709.75. GC-MS (70 eV) m/z (%): 270 (M⁺, 19), 236 (69), 207 (56), 189 (55), 179 (100), 107 (55).

4-Methoxy-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3e )^3,4

¹H NMR (400 MHz, CDCl₃): δ 2.36 (s, 3H), 3.84 (s, 3H), 6.68 (s, 1H), 6.93 (d, 2H, J 8.64 Hz), 6.92-6.87 (d, 2H, J 8.64 Hz), 11.64 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.62, 55.51, 107.43, 127.72, 128.84, 159.43, 164.41. IR (KBr) ν_max/cm^-1: 3145.67, 3001.02, 2960.52, 2839.01, 1606.59, 1510.15, 1467.72, 1427.22, 1334.64, 1247.85, 1182.28, 1157.20, 908.41, 825.47, 765.68, 684.68, 597.89, 532.31. GC-MS (70 eV) m/z (%): 240 (M⁺, 14), 206 (42), 159 (79), 134 (100), 107 (68), 77 (99).

4-[[1-(Methylthio)-2-nitroethenyl]amino]-phenol ( 3f )^16,17

¹H NMR (400 MHz, MeOD): δ 2.42 (s, 3H), 6.79 (s, 1H), 6.83 (d, 2H, J 9.24 Hz), 7.14 (d, 2H, J 9.24 Hz). ¹³C NMR (100 MHz, MeOD): δ 14.91, 108.08, 117.04, 129.27, 129.49, 159.16, 167.98. IR (KBr) ν_max/cm^-1: 3199.67, 3164.95, 3055.02, 2931.58, 1610.44, 1552.58, 1517.87, 1442.65, 1425.29, 1313.43, 1271.00, 1230.49, 1168.78, 906.48, 509.17. GC-MS (70 eV) m/z (%): 226 (M⁺, 9), 192 (20), 145 (55), 133 (89), 119 (47), 93 (55), 65 (100). (Found: C, 47.16; H, 4.74; N, 12.23; S, 13.45. Calc. for C₉H₁₀N₂O₃S: C, 47.78; H, 4.45; N, 12.38; S, 14.17%).

4-Fluoro-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3h )^9,16,17

¹H NMR (400 MHz, CDCl₃): δ 2.40 (s, 3H), 6.70 (s, 1H), 7.16-7.12 (m, 2H), 7.33 – 7.29 (m, 2H,), 11.67 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.67, 107.90, 116.35 and 116.57 (C-F), 128.30 and 128.39 (C-F), 132.14, 160.82 and 163.89 (C-F), 163.29. IR (KBr) ν_max/cm^-1: 3161.10, 3051.16, 3016.45, 1577.66, 1512.08, 1477.36, 1415.65, 1361.64, 1274.85, 1188.06, 914.19, 837.04, 761.83, 684.68. GC-MS (70 eV) m/z (%): 228 (M⁺, 7), 194 (11), 135 (54), 122 (45), 95 (100), 75 (47).

4-Bromo-N-[1-(methylthio)-2-nitroethenyl]-benzenamine ( 3j )¹⁹

¹H NMR (200 MHz, CDCl₃): δ 2.39 (s, 3H), 6.69 (s, 1H), 7.19 (d, 2H, J 8.77 Hz), 7.55 (d, 2H, J 8.77 Hz), 11.70 (s, 1H). ¹³C NMR (50 MHz, CDCl₃): δ 14.74, 108.32, 127.58, 131.06, 132.62, 135.30, 159.24. IR (KBr) ν_max/cm^-1: 3151.45, 3083.95, 3060.81, 1585.37, 1564.15, 1479.29, 1411.79, 1396.36, 1348.14, 1265.21, 1168.78, 1010.63, 910.33, 759.90, 678.89. GC-MS (70 eV) m/z (%): 290 (M+2, 5), 288 (M⁺, 6), 256 (16), 254 (16), 209 (44), 207 (44), 157 (68), 155 (69), 75 (100). (Found: C, 38.08; H, 3.49; N, 9.44; S, 10.44. Calc. for C₉H₉N₂O₂SBr: C, 37.38; H, 3.14; N, 9.69; S, 11.09%).

N-[1-(Methylthio)-2-nitroethenyl]-1,3-benzodioxol-5-amine ( 3l )¹⁶

¹H NMR (400 MHz, CDCl₃): δ 2.37 (s, 3H), 6.04 (s, 2H), 6.66 (s, 1H), 6.76-6.74 (m, 2H), 6.82 (d, 1H, J 8.08 Hz), 11.59 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.62, 107.82, 125.91, 128.10, 129.37, 138.18, 163.40. IR (KBr) ν_max/cm^-1: 3139.88, 3024.16, 2908.44, 1610.44, 1566.08, 1504.37, 1473.51, 1336.57, 1174.56, 1029.91, 867.90, 761.83. GC-MS (70 eV) m/z (%): 254 (M⁺, 16), 220 (57), 207 (24), 173 (83), 121 (100), 65 (87). (Found: C, 47.04; H, 4.25; N, 10.80; S, 11.47. Calc. for C₁₀H₁₀N₂O₄S: C, 47.24; H, 3.96; N, 11.02; S, 12.61%).

N-[1-(Methylthio)-2-nitroethenyl]-benzenamine ( 3m )^3,4,9,16-18

¹H NMR (400 MHz, CDCl₃): δ 2.38 (s, 3H), 6.70 (s, 1H), 7.45-7.27 (m, 5H), 11.81 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.67, 101.95, 107.54, 107.69, 108.35, 120.12, 129.94, 147.66, 148.29, 164.09. IR (KBr) ν_max/cm^-1: 3147.60, 2999.09, 1542.94, 1531.37, 1461.94, 1425.29, 1336.57, 1265.21, 1178.42, 896.83, 756.04, 690.47, 534.24. GC-MS (70 eV) m/z (%): 210 (M⁺, 10), 176 (8), 163 (16), 117 (69), 77 (100).

N-[1-(Methylthio)-2-nitroethenyl]-cyclohexanamine ( 5 )²⁰

¹H NMR (400 MHz, CDCl₃): δ 1.47-1.32 (m, 5H), 1.67-1.60 (m, 1H), 1.83 -1.74 (m, 2H), 2.05-1.95 (m, 2H), 2.44 (s, 3H), 3.67 (m, 1H), 6.56 (s, 1H), 10.59 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 14.34, 24.25, 25.07, 32.78, 53.79, 105.86, 163.29. IR (KBr) ν_max/cm^-1: 3136.02, 2993.30, 2927.73, 2852.51, 1564.15, 1461.94, 1423.36, 1348.14, 1315.36, 1218.92, 1081.99, 964.34, 852.47. GC-MS (70 eV) m/z (%): 216 (M⁺, 1), 182 (1), 135 (17), 83 (79), 55 (100).

Supplementary Information

Supplementary information is available free of charge at http://jbcs.org.br, as PDF file.

Acknowledgments

We acknowledge CAPES, FAPESP, CNPq and INBEQMeDI – INCT Program for financial support and fellowships.

Received: September 11, 2009

Web Release Date: February 4, 2010

Supplementary Information

• 1. Rao, H. S. P.; Geetha, K.; Tetrahedron Lett. 2009, 50, 3836.
• 2. Sukach, V. A.; Bolbut, A. V.; Petin, A. Y.; Vovk, M. V.; Synthesis 2007, 835.
• 3. Venkatesh, C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H.; Org. Lett. 2005, 7, 2169.
• 4. Sundaram, G. S. M.; Singh, B.; Venkatesh, C.; Ila, H.; Junjappa, H.; J. Org. Chem 2007, 72, 5020.
• 5. Cai, J.-J.; Zou, J.-P.; Pan, X.-Q.; Zhang, W.; Tetrahedron Lett. 2008, 49, 7386.
• 6. Guo,W.-X.; Jin, H.-L.; Chen, J.-X.; Chen, F.; Ding, J.-C.; Wu, H.-Y.; J. Braz. Chem. Soc. 2009, 20, 1674.
• 7. Glushkov, R. G.; Adamskaya, E. V.; Vosyakova, T. I.; Oleinik, A. F.; Pharmaceut. Chem. J. 1990, 24, 369.
• 8. Srinivasachari, R.; Tetrahedron 1999, 55, 7065.
• 9. Kearney, T.; Joule, J. A.; Jackson, A.; Heterocycles 1992, 33, 757.
• 10. Seager, J.F.; Dansey, R.; GB 2 160 204A, 1985
• 11. Deshmukh, A. R. A. S.; Reddy, T. I.; Bhawal, B.M.; Shiralkar, V. P.; Rajappa, S.; J. Chem. Soc., Perkin Trans. I 1990, 1217.
• 12. Prado, A. G. S.; Quim. Nova 2003, 26, 738.
• 13. Kappe, C. O.; Chem. Soc. Rev. 2008, 37, 1127.
• 14. Sanseverino, A. M.; Quim. Nova 2002, 25, 660.
• 15. Bueno, M. A.; Silva, L. R. S. P.; Correa, A. G.; J. Braz. Chem. Soc. 2008, 19, 1264.
• 16. Kato, F.; Miyata, K.; Kimura, H.; Yamamoto, K.; Ikegami, H.; Takeo, H.; WO 2000016766, 2000
• 17. Bernard, D.; Mauger, J.; Ruxer, J. M.; Martorana, P.; FR 2730733, 1996
• 18. Sone, M.; Tominaga, Y.; Matsuda, Y.; Kobayashi, G.; Yakugaku Zasshi 1977, 97, 262.
• 19. Zou, Y.; Feng, J.; Li, J.; Ye, C.; Synth. Met. 1995, 71, 1743.
• 20. Masereel, B.; J. Med. Chem. 1998, 41, 3239.
• 21. Kearney, T.; Harris, P.A.; Jackson, A.; Joule, J. A.; Synthesis 1992, 769.
• 22. Schaefer, H.; J. Prakt. Chem. 1977, 319, 149.

Publication Dates

• Publication in this collection
  13 July 2010
• Date of issue
  2010

History

• Accepted
  04 Feb 2010
• Received
  11 Sept 2009